Story
Gray Hair
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In one pass Hair turning white is not finished hair fading.
Educational content, not medical advice — consult a clinician.
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Chapter 1
Where hair color comes from
Hair turning white is not finished hair fading. It is the follicle no longer putting pigment into the stretch of hair it is making now.
Hair color is melanin. It is made by melanocytes, cells whose job is to make pigment, in the bulb at the base of the follicle, and handed to the neighboring cells that are turning into the hair strand. Black-brown and red-yellow melanin come in different proportions, which is what makes hair black, brown or red.
This pigment line runs only during the hair's growth phase. It shuts down in the regression phase and is absent in the resting phase. Every new hair needs a fresh crew of melanocytes in the bulb, and they are resupplied by a small group of melanocyte stem cells higher up in the follicle.
Once the strand grows out of the scalp it is keratin with no living cells, and its color was settled inside the follicle. So a white hair is white as it grows; it is not a dark hair slowly turning white on your head.
Hair color is melanin. It is made by melanocytes, cells whose job is to make pigment, in the bulb at the base of the follicle, and handed to the neighboring cells that are turning into the hair strand. Black-brown and red-yellow melanin come in different proportions, which is what makes hair black, brown or red.
This pigment line runs only during the hair's growth phase. It shuts down in the regression phase and is absent in the resting phase. Every new hair needs a fresh crew of melanocytes in the bulb, and they are resupplied by a small group of melanocyte stem cells higher up in the follicle.
Once the strand grows out of the scalp it is keratin with no living cells, and its color was settled inside the follicle. So a white hair is white as it grows; it is not a dark hair slowly turning white on your head.
Mechanism · What makes a hair gray or white
Look at a single hair. A white hair has none of the small pigment granules (melanosomes) at all; a gray hair still has some, just sparsely scattered. The keratin of the strand is pale yellow, and with no pigment in the way, light reflects and bends inside it, so it looks white.A salt-and-pepper head is mostly dark and white hairs mixed together: each follicle runs its own cycle and has its own reserve, and whichever runs out first turns white first.
The pigment unit in the bulb is small: one melanocyte serves only about 5 cells that are becoming the strand, while in the epidermis of the skin one melanocyte serves about 36 (Kumar review). And making pigment is itself a chemical line that involves oxidation, which matters in the chapter Hydrogen peroxide builds up.
How hair itself grows and sheds is a separate line in the same follicle; Hair Loss covers it.
Chapter 2
The pigment reserve runs out
Graying with age happens in roughly two steps, both inside the follicle.
The first is in the bulb. Hair after hair, the melanocytes there make less and less pigment. The key pigment-making enzyme, tyrosinase, loses activity, pigment fails to be handed on, and some melanocytes simply die off. At this stage hair first gets lighter, then gray.
The second is higher up in the follicle. The reserve of melanocyte stem cells that resupplies the melanocytes runs out too. In mice and in the follicles of older people, these stem cells, which should wait quietly, were seen maturing early in place and getting used up, so the reserve is not refilled. Once this happens, graying is largely irreversible (O'Sullivan review).
That is why hair that has turned white rarely darkens again: the follicle no longer has pigment-making cells to fill the gap.
The first is in the bulb. Hair after hair, the melanocytes there make less and less pigment. The key pigment-making enzyme, tyrosinase, loses activity, pigment fails to be handed on, and some melanocytes simply die off. At this stage hair first gets lighter, then gray.
The second is higher up in the follicle. The reserve of melanocyte stem cells that resupplies the melanocytes runs out too. In mice and in the follicles of older people, these stem cells, which should wait quietly, were seen maturing early in place and getting used up, so the reserve is not refilled. Once this happens, graying is largely irreversible (O'Sullivan review).
That is why hair that has turned white rarely darkens again: the follicle no longer has pigment-making cells to fill the gap.
Mechanism · Why the stem cells get stranded
Why the melanocyte stem cell reserve runs out earlier than other stem cells in the body is not settled. Two studies each supply one piece of the puzzle, both mainly in mice:Nishimura 2005 saw in mice and in the follicles of older people that aging melanocyte stem cells take on pigment and mature early, in the place where they should be resting, so they are spent while still in the reserve. When mice lacked Bcl2, a gene that keeps these stem cells alive, they grayed much earlier.Sun 2023 tracked single stem cells in mice and found that they normally move back and forth in the follicle, switching between a waiting state and a ready-to-work state; with age, more and more of them get stuck in place and stop producing melanocytes. The authors suggest that getting them moving again might be a new way to prevent graying, but this has not been tried in people.
Know the limits: these are mechanism studies. They answer why the reserve runs out, not what to eat to prevent it. The O'Sullivan review also points out that human graying starts in the bulb, that depletion of the stem cell reserve comes later, and that there is still no accepted complete model.
Chapter 3
Hydrogen peroxide builds up
Making pigment in the follicle is a chemical line that produces oxidizing by-products. One of them is hydrogen peroxide (the main ingredient of household peroxide), which catalase normally breaks down into water and oxygen.
A study of human hair and follicles (Wood 2009) found that gray and white hair shafts had built up hydrogen peroxide to millimolar concentrations, and that in Gray Hair follicles catalase and two enzymes that repair oxidative damage were barely detectable. The extra hydrogen peroxide oxidized an amino acid (methionine) in the active site of tyrosinase, so the enzyme worked worse and worse, and the color faded little by little.
Know how much weight it carries: the authors themselves say it supports an idea that has been voiced for a long time but is not yet proven enough. A review judges oxidative damage to be a likely major driver of graying, but there is still no accepted complete model of human graying (O'Sullivan review).
A study of human hair and follicles (Wood 2009) found that gray and white hair shafts had built up hydrogen peroxide to millimolar concentrations, and that in Gray Hair follicles catalase and two enzymes that repair oxidative damage were barely detectable. The extra hydrogen peroxide oxidized an amino acid (methionine) in the active site of tyrosinase, so the enzyme worked worse and worse, and the color faded little by little.
Know how much weight it carries: the authors themselves say it supports an idea that has been voiced for a long time but is not yet proven enough. A review judges oxidative damage to be a likely major driver of graying, but there is still no accepted complete model of human graying (O'Sullivan review).
Myth · Can antioxidant products reverse it
This mechanism is often used to sell things: tablets containing catalase, and anti-gray shampoos with added vitamins C and E.Following the mechanism, they have a long way to go. An enzyme taken by mouth is a protein and gets broken down in the gut. Shampoo stays on the scalp only briefly, and a review questions the effect of such additives (Kumar review). In Wood 2009, methionine blocked this oxidation only in a test tube; no treatment was tried in people.
More important is the step in The pigment reserve runs out: once the reserve is spent, even if oxidation is held down, there are no cells left to make pigment. No antioxidant product has been shown to make people's white hair dark again (O'Sullivan review).
Chapter 4
Can stress turn hair gray?
In mice, yes — and not through the stress hormones people usually name.
Zhang 2020 put mice through restraint, a run of unpredictable stressors, or pain, and all three kinds of stress gave them white fur. Tracing it back, the cause was the sympathetic nerves (the nerves that run the fight-or-flight response) wrapped around the melanocyte stem cells: under stress they release a burst of noradrenaline (norepinephrine), which forces the stem cells that should be resting to divide, mature and leave all at once. The reserve is emptied in one go, and the white fur is permanent. Removing the adrenal glands, which make stress hormones, or ruling out immune attack did not stop it.
Discount it when moving to people: this is a mouse experiment, and in people, stress and graying have so far only been seen moving together in small studies.
Zhang 2020 put mice through restraint, a run of unpredictable stressors, or pain, and all three kinds of stress gave them white fur. Tracing it back, the cause was the sympathetic nerves (the nerves that run the fight-or-flight response) wrapped around the melanocyte stem cells: under stress they release a burst of noradrenaline (norepinephrine), which forces the stem cells that should be resting to divide, mature and leave all at once. The reserve is emptied in one go, and the white fur is permanent. Removing the adrenal glands, which make stress hormones, or ruling out immune attack did not stop it.
Discount it when moving to people: this is a mouse experiment, and in people, stress and graying have so far only been seen moving together in small studies.
Mechanism · Why the white shows a cycle later
One detail in Zhang 2020 fits the chapter Where hair color comes from. Within 5 days of an injection of a pain-causing drug, many follicles in the mice had lost their melanocyte stem cells, yet the melanocytes already at work kept making pigment, and that round of fur stayed black. The white only showed when the next round of fur grew in with no new melanocytes to take over. When the researchers briefly held back stem cell division as the stress began, no white fur appeared: the damage happens at the moment the stem cells are forced to start up all together.Following this mechanism, hair already on your head does not turn white on the spot after a single fright. Reviews link so-called overnight whitening to alopecia areata (hair suddenly falling out in patches), telogen effluvium and vitiligo, among other causes (Kumar review); a dermatologist needs to tell these apart.
Evidence · Can a person's gray hair darken again
Rosenberg 2021 scanned the color along 397 hairs from 14 healthy people, reading each hair like tree rings for what happened while it grew. They found that some hairs that had turned white later grew a colored stretch again; compared with the life events the donors recalled, the times when individual hairs turned white and darkened again matched periods when stress rose and fell.Read it carefully: this is a small descriptive study. It shows only that this can happen, and that it can coincide with stress; it cannot show that stress caused it, or how common it is. Using a computer model, the authors suggest that only hairs already close to their graying threshold might darken again for a while as stress eases; by the mechanism in The pigment reserve runs out, a follicle whose reserve is spent has no way back.
What you can take from it: long-term stress is worth dealing with for the sake of your whole body, but don't expect lower stress to turn a gray head dark again.
Chapter 5
Genes, and causes worth checking
When graying starts and how fast it goes depends most on age; reviews generally hold that genes matter a lot, but how large their share is remains unclear (O'Sullivan review).
One specific site has been found, in the IRF4 gene: a genome-wide study of more than 6,000 Latin Americans linked it to graying, and IRF4 is one of the genes involved in switching on tyrosinase (Adhikari 2016). It is one piece of the puzzle, not a chart that tells you at what age you will go gray.
In a minority of cases, early graying comes together with a problem that can be found and treated:
Vitamin B12 deficiency, especially pernicious anemiaUnderactive thyroid: thyroid hormone itself pushes follicles to make pigmentVitiligo: it can turn a small lock of hair white in one spotSmoking: studies have seen smokers go gray earlier; this is an association
Most of this comes from small studies (Kumar review).
One specific site has been found, in the IRF4 gene: a genome-wide study of more than 6,000 Latin Americans linked it to graying, and IRF4 is one of the genes involved in switching on tyrosinase (Adhikari 2016). It is one piece of the puzzle, not a chart that tells you at what age you will go gray.
In a minority of cases, early graying comes together with a problem that can be found and treated:
Vitamin B12 deficiency, especially pernicious anemiaUnderactive thyroid: thyroid hormone itself pushes follicles to make pigmentVitiligo: it can turn a small lock of hair white in one spotSmoking: studies have seen smokers go gray earlier; this is an association
Most of this comes from small studies (Kumar review).
Numbers · How early counts as premature
By the standard the Kumar review cites, graying that starts before age 20 in white people or before 30 in people of African descent counts as premature graying; some authors suggest 25 for people from the Indian subcontinent, and there is no accepted line for Asian populations. The average age at which graying starts is about 34 in white people and about 43.9 in people of African descent.As for nutrition, the data in the review are thin:
In an older study, about 55% of patients with pernicious anemia had started graying before 50, compared with 30% of controls.Studies of copper, iron, zinc and vitamin D disagree: one found lower blood copper in people with premature graying but not lower zinc or iron; another, in young Indians, found lower , calcium and vitamin D. These are observed associations and cannot show that these nutrients caused it.
So some authors suggest that people who gray very early, with no one in the family who did, could have their B12, folate and thyroid checked.
Chapter 6
Dyes and supplements: what holds up
For hair that has grayed with age, no drug or supplement has been shown to make it dark again (O'Sullivan review). The real options are these:
Hair dye: still the main option. It colors only the strands that have already grown out and does not reach the follicle. Permanent dyes can damage the strand; a few people develop dermatitis from p-phenylenediamine (PPD), a common dye ingredient, and some lose hair after dyeing (Kumar review). If your scalp turns red, itchy or breaks out in a rash after dyeing, stop using it and see a dermatologist; if your lips, tongue or throat suddenly swell, or you struggle to breathe or swallow, call emergency services now.Supplements: biotin, calcium pantothenate, zinc, copper and selenium have all been tried, and none gave promising results (Kumar review).Treat a real deficiency: if tests find B12 deficiency or an underactive thyroid, follow your doctor's treatment, which matters for your health in its own right; whether the hair color comes back is not guaranteed.
Hair dye: still the main option. It colors only the strands that have already grown out and does not reach the follicle. Permanent dyes can damage the strand; a few people develop dermatitis from p-phenylenediamine (PPD), a common dye ingredient, and some lose hair after dyeing (Kumar review). If your scalp turns red, itchy or breaks out in a rash after dyeing, stop using it and see a dermatologist; if your lips, tongue or throat suddenly swell, or you struggle to breathe or swallow, call emergency services now.Supplements: biotin, calcium pantothenate, zinc, copper and selenium have all been tried, and none gave promising results (Kumar review).Treat a real deficiency: if tests find B12 deficiency or an underactive thyroid, follow your doctor's treatment, which matters for your health in its own right; whether the hair color comes back is not guaranteed.
Myth · Can He Shou Wu or black sesame darken hair
The two most common hair-darkening claims in Chinese-speaking communities:He Shou Wu (Polygonum multiflorum): often taken to darken graying hair and to tonify the liver and kidneys, but the US National Institutes of Health's database on drug-induced liver injury lists it as a well-established cause of clinically apparent liver injury; of clinically apparent He Shou Wu liver injuries, about 10% ended in death or urgent liver transplantation (LiverTox 2020). Risking your liver for hair color is not worth it. Why some people take it without trouble while others injure their liver within months is explained in Herb Safety · natural doesn't mean safe.Black sesame: it simply has more dark pigment in its seed coat, and there is no reliable human evidence that it darkens hair. Following the mechanism, pigment you eat is broken down in the gut and is not delivered to the follicle to color hair.
Back to the mechanism: hair color is made on the spot by the melanocytes in the follicle, relying on them and the stem cell reserve behind them, and color you eat cannot reach them.
Chapter 7
When to see a doctor
Most gray hair is a matter of age and genes and needs no medical care. These situations are worth having a doctor see you in person:
Gray hair together with numbness or pins and needles in the hands and feet, unsteady walking, marked tiredness, or a sore or red tongue: this may be vitamin B12 deficiency, so see a doctor soon for a blood test; the longer it goes on, the more likely nerve damage becomes permanent.Gray hair together with extreme tiredness, feeling the cold more than usual, weight gain and constipation: a doctor may check your thyroid.White hair growing from a patch of pale skin, or more and more white patches on the skin: see a dermatologist to check for vitiligo.Hair turning white suddenly over a large area, or falling out in patches at the same time: see a dermatologist to tell the causes apart.Gray hair in a child, or graying a lot at a young age when no one in the family did: tell a doctor, who can check B12, folate and thyroid.
This story is education and does not replace a diagnosis.
Gray hair together with numbness or pins and needles in the hands and feet, unsteady walking, marked tiredness, or a sore or red tongue: this may be vitamin B12 deficiency, so see a doctor soon for a blood test; the longer it goes on, the more likely nerve damage becomes permanent.Gray hair together with extreme tiredness, feeling the cold more than usual, weight gain and constipation: a doctor may check your thyroid.White hair growing from a patch of pale skin, or more and more white patches on the skin: see a dermatologist to check for vitiligo.Hair turning white suddenly over a large area, or falling out in patches at the same time: see a dermatologist to tell the causes apart.Gray hair in a child, or graying a lot at a young age when no one in the family did: tell a doctor, who can check B12, folate and thyroid.
This story is education and does not replace a diagnosis.
References · 12
- Kumar, A. B., Shamim, H., & Nagaraju, U. (2018). Premature graying of hair: review with updates. International Journal of Trichology, 10(5), 198-203. Narrative review. Premature graying is defined as graying before 20 years in Caucasians and before 30 years in African Americans (average onset 34 and 43.9 years); hair is pigmented only in anagen, melanogenesis is switched off in catagen and absent in telogen; a definition for Asian populations is lacking, and some authors suggest 25 years for the Indian subcontinent; each bulb melanocyte serves about 5 keratinocytes versus 36 in the epidermis; white hair lacks melanosomes, grey hair has sparse ones. Associations reported, mostly from small case-control or older studies: vitamin B12 deficiency (about 55% of patients with pernicious anemia grayed before 50 versus 30% of controls), low thyroid hormone, vitiligo, smoking, lower copper in one study that did not find lower zinc or iron, and lower ferritin, calcium and vitamin D3 in a study of young Indians; the exact cause remains unknown. Treatment should address the cause (B12 or thyroid replacement); vitamins and minerals such as biotin, calcium pantothenate, zinc, copper and selenium have not given promising results; hair dyes remain the main option, and some people get irritant dermatitis (commonly from p-phenylenediamine) or hair loss from dyeing. Some authors suggest testing serum B12, folic acid and thyroid in people with no family history of premature graying. Sudden whitening (canities subita) has been associated with alopecia areata, telogen effluvium, vitiligo and psychogenic causes. 10.4103/ijt.ijt_47_18
- O'Sullivan, J. D. B., Nicu, C., Picard, M., Chéret, J., Bedogni, B., Tobin, D. J., & Paus, R. (2021). The biology of human hair greying. Biological Reviews, 96(1), 107-128. Narrative review. Human greying invariably begins with a gradual decline in melanogenesis in the anagen hair bulb (reduced tyrosinase activity, defective melanosome transfer, apoptosis of bulb melanocytes), so it is a primary event of the bulb, not the bulge; eventually the bulge melanocyte stem cell pool becomes depleted as well, at which stage greying becomes largely irreversible. Oxidative damage likely is a crucial driver. But there is still no universally accepted model of human hair greying, the extent of genetic contributions remains unclear, and how psychoemotional stress impacts the process, and how to retard or reverse greying, are open questions. 10.1111/brv.12648
- Nishimura, E. K., Granter, S. R., & Fisher, D. E. (2005). Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science, 307(5710), 720-724. Using melanocyte-tagged transgenic mice and aging human hair follicles, hair graying is caused by defective self-maintenance of melanocyte stem cells in the bulge niche; physiologic aging of melanocyte stem cells was associated with ectopic pigmentation or differentiation within the niche (the reserve cells mature where they should stay dormant), accelerated by Mitf mutation, and Bcl2 deficiency causes selective apoptosis of the stem cells. Mostly mouse genetics; the human part is histology of aging follicles, not an intervention. 10.1126/science.1099593
- Rosenberg, A. M., Rausser, S., Ren, J., Mosharov, E. V., Sturm, G., Ogden, R. T., Patel, P., Kumar Soni, R., Lacefield, C., Tobin, D. J., Paus, R., & Picard, M. (2021). Quantitative mapping of human hair greying and reversal in relation to life stress. eLife, 10, e67437. 397 hairs from 14 healthy donors (aged 9-65) were profiled for pigment along their length. White/grey hairs that naturally regain pigmentation were found across sex, ethnicities, ages and body regions; greying and reversal can occur in parallel with self-reported psychological stressors; grey hairs upregulated proteins of energy metabolism, mitochondria and antioxidant defenses; a computational model suggests a threshold-based mechanism for temporary reversibility, most likely in hairs near their greying threshold. A small descriptive study: it shows that reversal happens and can coincide with stress, not that stress causes greying or how common reversal is. 10.7554/eLife.67437
- Sun, Q., Lee, W., Hu, H., Ogawa, T., De Leon, S., Katehis, I., Lim, C. H., Takeo, M., Cammer, M., Taketo, M. M., Gay, D. L., Millar, S. E., & Ito, M. (2023). Dedifferentiation maintains melanocyte stem cells in a dynamic niche. Nature, 616(7958), 774-782. In mice, live imaging, single-cell RNA sequencing and lineage tracing showed that most melanocyte stem cells move between the hair follicle stem cell and transit-amplifying compartments and reversibly change differentiation state under local cues such as WNT; the system is maintained by reverted cells rather than a reserve exempt from change. During ageing, stranded stem cells accumulate that no longer contribute melanocyte progeny. The authors suggest modulating stem-cell mobility as a possible approach to preventing greying; nothing was tested in people. 10.1038/s41586-023-05960-6
- Wood, J. M., Decker, H., Hartmann, H., Chavan, B., Rokos, H., Spencer, J. D., Hasse, S., Thornton, M. J., Shalbaf, M., Paus, R., & Schallreuter, K. U. (2009). Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair. FASEB Journal, 23(7), 2065-2075. Human gray/white scalp hair shafts accumulate hydrogen peroxide in millimolar concentrations (FT-Raman in vivo); catalase and methionine sulfoxide reductase A and B protein are almost absent in the gray hair follicle; oxidation of methionine residues, including Met 374 in the active site of tyrosinase, limits the enzyme and leads to gradual loss of hair color. The authors frame this as support for a long-voiced but insufficiently proven concept; L-methionine prevented the oxidation only in vitro, and no treatment was tested in people. 10.1096/fj.08-125435
- Zhang, B., Ma, S., Rachmin, I., He, M., Baral, P., Choi, S., Gonçalves, W. A., Shwartz, Y., Fast, E. M., Su, Y., Zon, L. I., Regev, A., Buenrostro, J. D., Cunha, T. M., Chiu, I. M., Fisher, D. E., & Hsu, Y.-C. (2020). Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature, 577(7792), 676-681. In mice, restraint stress, chronic unpredictable stress and pain induced by resiniferatoxin all produced white hairs. The stress-induced loss of melanocyte stem cells was independent of immune attack or adrenal stress hormones: sympathetic nerves innervating the niche release a burst of noradrenaline that drives quiescent melanocyte stem cells to proliferate rapidly, then differentiate, migrate and be permanently depleted. After resiniferatoxin many follicles lost their stem cells within 5 days while the existing coat stayed black; transient suppression of stem-cell proliferation prevented greying. Mouse study; noradrenaline also switched on proliferation and differentiation genes in cultured human melanocytes, but greying in people was not studied. 10.1038/s41586-020-1935-3
- Adhikari, K., Fontanil, T., Cal, S., Mendoza-Revilla, J., Fuentes-Guajardo, M., Chacón-Duque, J. C., et al. (2016). A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. Nature Communications, 7, 10815. Genome-wide association scan in over 6,000 Latin Americans; reported the first locus for hair greying, SNP rs12203592 in IRF4, a gene that works with MITF in switching on tyrosinase, the key enzyme of melanin synthesis; age was the trait most correlated with greying (r = 0.56). An association study: it finds one locus, and does not say how much of greying is genetic. 10.1038/ncomms10815
- National Institute of Diabetes and Digestive and Kidney Diseases. (2020). Polygonum multiflorum. In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: NIDDK. Likelihood score A; latency a few days to ~6 months; ~10% of clinically apparent cases were fatal or required urgent liver transplantation. www.ncbi.nlm.nih.gov/books/NBK548795
- NHS. (2025). Hair dye reactions. Many permanent and some semi-permanent hair dyes contain PPD (paraphenylenediamine), which can irritate the skin or cause an allergic reaction; for a mild reaction stop using the dye and wash it off, and a pharmacist or GP can help. Call 999 if your lips, mouth, throat or tongue suddenly become swollen, you are breathing very fast or struggling to breathe, your throat feels tight or you are struggling to swallow, or your skin, tongue or lips turn blue, grey or pale (page last reviewed 29 December 2025). www.nhs.uk/conditions/hair-dye-reactions
- NHS. (2023). Vitamin B12 or folate deficiency anaemia: symptoms. Symptoms usually develop gradually and include feeling weak or tired, shortness of breath, headaches, palpitations, a sore or red tongue sometimes with mouth ulcers, and problems with memory; vitamin B12 deficiency can also cause neurological symptoms including numbness, pins and needles, muscle weakness, and problems with balance and coordination. See a GP if you have these symptoms; diagnosis and treatment as soon as possible matters, because some problems can be irreversible if left untreated. www.nhs.uk/conditions/vitamin-b12-or-folate-deficiency-anaemia/symptoms
- NHS. (2025). Underactive thyroid (hypothyroidism): symptoms. Symptoms may be mild and hard to notice; common symptoms include extreme tiredness, feeling cold more than usual, weight gain, constipation, difficulty concentrating, low mood. www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/symptoms